Morephantin derivatives useful in cancer treatment

Abstract

Formula I: [Formula 1] TIFF2024517443000025.tif3259[where, R 1 and R 2 is as defined herein. Use of said compounds in the treatment of disease is also disclosed.

Description

[Technical Field]

[0001] This invention relates to molephantin derivatives, pharmaceutical formulations containing molephantin derivatives, and the medical use of molephantin derivatives (for example, in the treatment of cancers such as colorectal cancer and gastric cancer). [Background technology]

[0002] The list or discussion of prior art in this specification should not necessarily be construed as an admission that the documents are part of the prior art or common technical knowledge.

[0003] Today, more than 60% of anticancer drugs are derived in some way from plants. Notable plant-derived anticancer drugs used in clinical practice include the vinca alkaloids vinblastine and vincristine, the camptothecin derivatives topotecan and irinotecan, and paclitaxel (Taxol), which are isolated from or derived from Catharanthus roseus G. Don. (Apocynaceae), Camptotheca acuminate Decne (Cornaceae), and Taxus brevifolia Nutt. (Taxaceae), respectively. However, these drugs are often associated with side effects such as alopecia, skin reactions, fatigue, and muscle / arthralgia.

[0004] The number of new cancer cases in low- and middle-income countries is projected to increase by more than 80% by 2040. Given this increase, along with the problems of drug resistance and adverse side effects of current treatments, new and effective anticancer drugs are needed.

[0005] Elephantopus tomentosus Linn. is a perennial flowering plant belonging to the Asteraceae family. Native to North America, it has spread widely throughout the pantropics. In Malaysia, the extract of the entire plant is used as a diuretic, analgesic, antipyretic, anthelmintic, and anti-inflammatory agent. The leaves of the plant are also used externally to relieve pain.

[0006] Phytochemical studies of E. tomentosus L. have isolated compounds such as triterpenes, flavonoids, alkaloids, caffeoylquinic acid, and sesquiterpene lactones. Tomenphantopin A and B are two of the earliest sesquiterpene lactones isolated from E. tomentosus L., and were found in human KB oral cancer cells at ED concentrations of 2.5 μg / ml and 5.0 μg / ml, respectively. 50 Cytotoxic activity was observed at the ED (Hayashi T, et al., Phytochemistry, vol. 26, 1987, 1065-1068). Since then, many other sesquiterpene lactones have been isolated. Tomenphantine A and B were isolated at ED concentrations of 3.0 μg / ml and 2.7 μg / ml, respectively. 50 It was found that the concentration of tomenfantopine D suppresses the proliferation of KB cell lines (Hayashi T, et al., J Nat Prod, vol. 62, 1999, 302-304). Tomenfantopine D and morephanthin have inhibitory activity against the human myeloid leukemia cell line K562 and the human hepatocellular carcinoma cell line (SMMC-7221), and for tomenfantopine D, IC25 levels of 44.8 μM and 11.2 μM were found to suppress the proliferation of KB cell lines. 50 For the IC50 values ​​of molephantine, the IC50 values ​​were 7.9 μM and 5.8 μM, respectively. 50 Although the values ​​were positive, tomenphantopine C, E, and F were inactive (Mei WL et al., Two new Germacranolides from Elephantopus tomentosus, Phytochemistry Letters, vol. 5, 2012, 800-803 and Wang B, et al., Two New Sesquiterpene Lactones from Elephantopus tomentosus, Chinese Journal of Chemistry, vol. 30, 2012, 1320-1322).

[0007] Multiple bioactive compounds isolated from E. tomentosus L have shown cancer cytotoxicity and antitumor activity, but these compounds have not yet been evaluated in clinical trials. There is also a lack of in vitro studies on the mechanistic action of these compounds, as well as in vivo studies in animal models. Therefore, it is currently impossible to predict whether any of the bioactive compounds isolated from E. tomentosus are actually effective in treating cancer in vivo or not. Summary of the Invention

[0008] The present invention relates to derivatives of mofrefantin, which may be isolated from E. tomentosus L itself. The derivatives may be prepared by esterification and, surprisingly, have improved anti-cancer activity both in vitro and in vivo.

[0009] Therefore, the present invention provides the following numbered clauses.

[0010] Clause 1. Formula I:

Chemical formula

[0011] Article 2. R 1 and R 2 However, each is independent of H and -C(O)R. 3 , or -C(O)C 1-3 Alkyl groups are shown, where the latter group is either unsubstituted or halo and R. 4 It is replaced by one or more elements selected from, Alternatively, R 1 However, -C(O)R 3 or -C(O)C 1-3 Alkyl groups are shown, where the latter group is either unsubstituted or halo and R. 4 It is substituted by one or more groups selected from R 2 However, it shows -C(O)C(=CH2)CH3, and by arbitrary choice, R 1 and R 2 However, each is independent of -C(O)R 3 or -C(O)C 1-3 Alkyl groups are shown, where the latter group is either unsubstituted or halo and R. 4It is replaced by one or more elements selected from, Alternatively, R 1 However, -C(O)R 3 or -C(O)C 1-3 Alkyl groups are shown, where the latter group is either unsubstituted or halo and R. 4 It is substituted by one or more groups selected from R 2 However, it shows -C(O)C(=CH2)CH3. A compound of formula I as described in Clause 1, or a pharmaceutically acceptable salt or solvate thereof.

[0012] Article 3. R 3 However, if present, it indicates an aryl or heterocyclic ring system, where each of the aryl and heterocyclic ring systems is either unsubstituted or NO2, in particular halo and C. 1-3 It is substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups are either unsubstituted or substituted with one or more halo groups. A compound of formula I as described in clause 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

[0013] Article 4. R 3 However, if present, it is an aryl, where the aryl is either unsubstituted or NO2, in particular halo and C 1-3 It is substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups are either unsubstituted or substituted with one or more halo groups. A compound of formula I as described in Clause 3, or a pharmaceutically acceptable salt or solvate thereof.

[0014] Article 5. R 3However, if present, it is phenyl, where phenyl is either unsubstituted or substituted with one or more groups selected from NO2, particularly F and C1 alkyl, where C1 alkyl is either unsubstituted or substituted with one or more halo groups. A compound of formula I as described in Clause 4, or a pharmaceutically acceptable salt or solvate thereof.

[0015] Article 6. R 2 However, it shows -C(O)C(=CH2)CH3. A compound of formula I as described in any one of clauses 1 to 5, or a pharmaceutically acceptable salt or solvate thereof.

[0016] Article 7. R 1 However, -C(O)R 3 Show, R 2 However, -C(O)R 3 Alternatively, it represents -C(O)C(=CH2)CH3. A compound of formula I as described in any one of clauses 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

[0017] Article 8. The following compounds: [Table 1] [Table 2] Selected from a list consisting of, A compound of formula I as described in Clause 1, or a pharmaceutically acceptable salt or solvate thereof.

[0018] Article 9. The following compounds: [Table 3] [Table 4] Selected from a list consisting of, A compound of formula I as described in Clause 8, or a pharmaceutically acceptable salt or solvate thereof.

[0019] Article 10. A pharmaceutical formulation comprising a compound of formula I as defined in any one of clauses 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, in a mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0020] Article 11. A compound of formula I as defined in any one of clauses 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for use in pharmaceuticals.

[0021] Article 12. Use of a compound of formula I as defined in any one of clauses 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a drug for the treatment of cancer.

[0022] Article 13. A compound of formula I as defined in any one of clauses 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer.

[0023] Article 14. A method for treating cancer, characterized by administering an effective amount of a compound of formula I as defined in any one of clauses 1 to 9, or a pharmaceutically acceptable salt or solvate thereof.

[0024] Article 15. The aforementioned cancers include adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumors, CNS tumors, breast cancer, Castleman disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, and gastric cancer. Cancer, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, renal cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g., acute lymphoblastic, acute myeloid, chronic lymphoblastic, chronic myeloid, chronic myelomonocytic), liver cancer, lung cancer (e.g., small cell or non-small cell), pulmonary carcinoid tumors, lymphoma (e.g., cutaneous), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, stomach cancer Use as described in Clause 12, the compound as described in Clause 13, or the method as described in Clause 14, selected from one or more of the group selected from cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms' tumor.

[0025] Article 16. The use, compound, or method described in Clause 15, wherein the cancer is selected from colorectal cancer and gastric cancer. [Brief explanation of the drawing]

[0026] [Figure 1A] Figures 1A-B show dose-response curves for different cancer cell lines to generate absolute IC50 values ​​for compounds NYH001-NYH005. [Figure 1B] Figures 1A-B show dose-response curves for different cancer cell lines to generate absolute IC50 values ​​for compounds NYH001-NYH005. [Figure 1C] Figures 1A-B show dose-response curves for different cancer cell lines to generate absolute IC50 values ​​for compounds NYH001-NYH005. [Figure 2A]Figures 2A-E show cloning assays illustrating colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent the standard errors of the mean values ​​from three independent experiments: *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2B] Figures 2A-E show cloning assays illustrating colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent the standard errors of the mean values ​​from three independent experiments: *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2C] Figures 2A-E show cloning assays illustrating colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent the standard errors of the mean values ​​from three independent experiments: *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2D] Figures 2A-E show cloning assays illustrating colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent the standard errors of the mean values ​​from three independent experiments: *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2E] Figures 2A-E show cloning assays illustrating colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent the standard errors of the mean values ​​from three independent experiments: *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 3] Figure 3 shows live-cell imaging of DLD-1 cells treated with DMSO (control) or compound NYH001-0003. Proliferation inhibition, mitotic arrest, and cell death were induced in cells treated with the compound. [Figure 4A]Figures 4A-D show that NYH001-NYH005 inhibits cancer cell migration in the Transwell migration assay. The figures show representative images of migrating cells (scale bar = 50 μm) and quantitative analysis of migrating cells after elution of crystal violet stain and measurement of absorbance at 590 nm. Data were taken from three independent experiments and are shown as mean ± SEM. *P≦0.05, **P≦0.01, and ***P≦0.001 [Figure 4B] Figures 4A-D show that NYH001-NYH005 inhibits cancer cell migration in the Transwell migration assay. The figures show representative images of migrating cells (scale bar = 50 μm) and quantitative analysis of migrating cells after elution of crystal violet stain and measurement of absorbance at 590 nm. Data were taken from three independent experiments and are shown as mean ± SEM. *P≦0.05, **P≦0.01, and ***P≦0.001 [Figure 4C] Figures 4A-D show that NYH001-NYH005 inhibits cancer cell migration in the Transwell migration assay. The figures show representative images of migrating cells (scale bar = 50 μm) and quantitative analysis of migrating cells after elution of crystal violet stain and measurement of absorbance at 590 nm. Data were taken from three independent experiments and are shown as mean ± SEM. *P≦0.05, **P≦0.01, and ***P≦0.001 [Figure 4D] Figures 4A-D show that NYH001-NYH005 inhibits cancer cell migration in the Transwell migration assay. The figures show representative images of migrating cells (scale bar = 50 μm) and quantitative analysis of migrating cells after elution of crystal violet stain and measurement of absorbance at 590 nm. Data were taken from three independent experiments and are shown as mean ± SEM. *P≦0.05, **P≦0.01, and ***P≦0.001 [Figure 5A]Figures 5A-B show that NYH001-NYH005 inhibit cancer cell invasion. The figure shows representative images of invading cells (scale bar = 50 μm) and quantitative analysis of invading cells after elution of crystal violet stain and measurement of absorbance at 590 nm. [Figure 5B] Figures 5A-B show that NYH001-NYH005 inhibit cancer cell invasion. The figure shows representative images of invading cells (scale bar = 50 μm) and quantitative analysis of invading cells after elution of crystal violet stain and measurement of absorbance at 590 nm. [Figure 6] Figure 6 shows that NYH001-NYH005 induces G2 / M and S phase cell cycle arrest in DLD-1 cells. DLD-1 cells treated with DMSO or the compound for 24 hours were analyzed by flow cytometry to determine the cell cycle distribution. [Figure 7] Figure 7 shows the dose-dependent effects of compounds NYH001-003 on the expression of apoptosis and autophagy-related proteins in DLD-1 cells. Cells were treated with DMSO and 1, 2.5, and 5 μM of either NYH001, 002, or 003 for 24 hours. Western blotting was performed to check the protein levels of cleaved PARP, cleaved caspases 3 and 7, LC3B, and ATG7. β-tubulin was used as a loading control. [Figure 8] Figure 8 shows images of dose-dependent inhibition of DLD-1 tumor spheroid growth after treatment with DMSO (control) or compound NYH001-003. [Figure 9] Figure 9 shows a plot of dose-dependent inhibition of DLD-1 tumor spheroid growth treated with DMSO (control) or compound NYH001-003. [Figure 10A] Figure 10 shows that NYH001-NYH003 can inhibit cell motility in a dose-dependent manner. [Figure 10B] Figure 10 shows that NYH001-NYH003 can inhibit cell motility in a dose-dependent manner. [Figure 10C]Figure 10 shows that NYH001-NYH003 can inhibit cell motility in a dose-dependent manner. [Figure 11] Figure 11 shows that NYH002 treatment suppresses tumor growth in the HCT116 cell xenograft model of Example 9. Mice were treated with either vehicle control, NYH001 (25 mg / kg), NYH002 (25 mg / kg), or 5-Fu (25 mg / kg). (A) Tumor volume over the entire duration of the experiment. The dots indicate the average tumor volume in each experimental group. (B) Representative photographs of tumors isolated at the end of the experiment for each experimental group. Scale bar is 10 mm. (C) Average tumor volume at the end of the experiment. (D) Average tumor weight at the end of the experiment. (E) Body weight of mice over the entire duration of the experiment. The dots indicate the average body weight of mice in each treatment group. All error bars indicate SEM, n=5. *P≦0.05, **P≦0.01, comparison between NYH002 and vehicle control. [Figure 12] Figure 12 shows that NYH002 treatment suppresses tumor growth in the DLD-1 cell xenograft model of Example 9. Mice were treated with either vehicle control, NYH002 (25 mg / kg), or 5-Fu (25 mg / kg). (A) Tumor volume over the entire duration of the experiment. The dots indicate the average tumor volume in each experimental group. (B) Representative photographs of tumors isolated at the end of the experiment for each experimental group. Scale bar is 10 mm. (C) Average tumor volume at the end of the experiment. (D) Average tumor weight at the end of the experiment. (E) Body weight of mice over the entire duration of the experiment. The dots indicate the average body weight of mice in each treatment group. All error bars indicate SEM, n=4. *P≦0.05, **P≦0.01, comparison between NYH002 and vehicle control. [Modes for carrying out the invention]

[0027] This invention relates to formula I: [ka] [In the formula, R 1 and R 2These are H and -C(O)R, respectively, independently. 3 , or -C(O)C 1-6 Alkyl groups are shown, where the latter group is either unsubstituted or halo and R. 4 It is replaced by one or more elements selected from, Alternatively, R 1 is -C(O)R 3 or -C(O)C 1-6 Alkyl groups are shown, where the latter group is either unsubstituted or halo and R. 4 It is substituted by one or more groups selected from R 2 This represents -C(O)C(=CH2)CH3, R 3 If present, indicates an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is either unsubstituted or contains NO2, in particular halo and C. 1-3 It is substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups are either unsubstituted or substituted with one or more halo groups. R 4 If present, indicates an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is either unsubstituted or halo and C 1-3 It is substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups are either unsubstituted or substituted with one or more halo groups. Compounds thereof, or pharmaceutically acceptable salts or solvates thereof To provide.

[0028] Therefore, R 1 H, -C(O)R 3 , or -C(O)C 1-6 Alkyl groups may also be represented, where the latter group is unsubstituted or halo and R 4 It is substituted by one or more groups selected from R2 When it represents -C(O)C(=CH2)CH3, R 1 is -C(O)R 3 or -C(O)C 1-6 alkyl, where the latter group may be unsubstituted or substituted by one or more groups selected from halo and R 4 and is so.

[0029] In other words, when R 2 represents -C(O)C(=CH2)CH3, R 1 is not H.

[0030] In some embodiments of the invention that may be referred to herein, R 1 is -C(O)R 3 or -C(O)C 1-6 alkyl, where the latter group may be unsubstituted or substituted by one or more groups selected from halo and R 4 and is so.

[0031] In some embodiments of the invention that may be referred to herein, R 2 may represent -C(O)C(=CH2)CH3.

[0032] In some embodiments of the invention that may be referred to herein, R 1 and R 2 may each independently be H, -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or substituted by one or more groups selected from halo and R 4 and may be so.

[0033] In some such embodiments, R 1 and R 2 may each independently be -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or substituted by halo and R4 may be substituted by one or more groups selected from

[0034] In some embodiments of the invention that may be referred to herein, R 1 is -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or substituted by one or more groups selected from halo and R 4 and R 2 may be -C(O)C(=CH2)CH3.

[0035] In some such embodiments, R 1 is -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or substituted by one or more groups selected from halo and R 4 and R 2 may be -C(O)C(=CH2)CH3.

[0036] In some embodiments of the invention that may be referred to herein, R 1 may be -C(O)R 3 and R 2 may be -C(O)R 3 or -C(O)C(=CH2)CH3.

[0037] R 3 , when present, represents aryl, cycloalkyl, or a heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is either unsubstituted or substituted by one or more groups selected from NO2, particularly halo and C 1-3 alkyl, where C 1-3 alkyl is either unsubstituted or substituted by one or more halo groups.

[0038] In some embodiments of the present invention, which may be referred to herein, R 3 If present, may represent an aryl or heterocyclic ring system, where each of the aryl and heterocyclic ring systems is unsubstituted, but is not limited to NO2, in particular halo and C. 1-3 It may be substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups may be unsubstituted or substituted with one or more halo groups.

[0039] In some embodiments of the present invention, which may be referred to herein, R 3 If present, it may be an aryl, where the aryl is unsubstituted or NO2, in particular halo and C 1-3 It is substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups are either unsubstituted or substituted with one or more halo groups.

[0040] In some embodiments of the present invention, which may be referred to herein, R 3 If present, this may be phenyl, where phenyl may be unsubstituted or substituted with one or more groups selected from NO2, particularly F and C1 alkyl, where C1 alkyl may be unsubstituted or substituted with one or more halo groups.

[0041] In any of the embodiments of the present invention described above, R 3 The substituents present above may be replaced by substituents other than NO2. In other words, in any of the embodiments of the present invention described above, R 3 may represent an aryl, cycloalkyl, or heterocyclic ring system (e.g., an aryl or heterocyclic ring system, e.g., an aryl (e.g., phenyl)), where each of aryl, cycloalkyl, heterocyclic ring system, and phenyl may be unsubstituted, or represent a halo (e.g., F) and C. 1-3It may be substituted with one or more groups selected from alkyl groups (e.g., C1 alkyl), where C 1-3 The alkyl (or C1 alkyl) is either unsubstituted or substituted with one or more halo (e.g., F) groups.

[0042] R 4 If present, indicates an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is either unsubstituted or halo and C 1-3 It is substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups are either unsubstituted or substituted with one or more halo groups.

[0043] In some embodiments of the present invention, which may be referred to herein, R 4 If present, this may represent an aryl or heterocyclic ring system, where each of the aryl and heterocyclic ring systems is unsubstituted, but also represents a halo and C 1-3 It may be substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups may be unsubstituted or substituted with one or more halo groups.

[0044] In some embodiments of the present invention, which may be referred to herein, R 4 If present, it may be an aryl, where the aryl is either unsubstituted or a halo and C 1-3 It is substituted with one or more groups selected from alkyl groups, where C 1-3 Alkyl groups are either unsubstituted or substituted with one or more halo groups.

[0045] In some embodiments of the present invention, which may be referred to herein, R 4If present, this may be phenyl, where phenyl may be unsubstituted or substituted with one or more groups selected from F and C1 alkyl, where C1 alkyl may be unsubstituted or substituted with one or more halo groups.

[0046] R 4 In some embodiments of the present invention, it may exist as a substituent on the methyl group. For example, C 1-6 Alkyl portion and R 4 This may include a substituted or unsubstituted benzyl group, where the substituents are as defined above.

[0047] Where the above group is referred to as containing "one or more" substituents, it may be substituted with one substituent or two or more substituents, for example, it may be substituted with 1 to 6 substituents, for example 1 to 5 substituents, for example 1; 2; or 3 substituents.

[0048] For example, alkyl groups (such as methyl C) 1-3 When an alkyl group is substituted with one or more substituents (e.g., halo groups), the alkyl group may be substituted with one, two, or three substituents (e.g., halo groups). The halo group may be a fluoro group. An example of an alkyl group substituted with one or more halo (e.g., fluoro) groups is trifluoromethyl.

[0049] As a further example, when an aryl group (e.g., a phenyl group) is substituted with one or more substituents, the aryl group has 1 to 5 substituents (e.g., a halo group or C). 1-3 Alkyl alkyl group, where C 1-3 The alkyl group itself may be substituted (as defined above, it may be substituted or unsubstituted). The aryl group may be a phenyl group. The halo group may be a fluoro group. C 1-3Alkyl groups may be as defined above. An example of an aryl group (e.g., a phenyl group) substituted with one or more halo (e.g., fluoro) groups is pentafluorophenyl.

[0050] Specific compounds according to the present invention include the following: [Table 5] [Table 6] This also includes pharmaceutically acceptable salts and solvates thereof.

[0051] In one embodiment of the present invention, the compound of formula I is as follows: ●The above compounds (a) to (f); ●The above compounds (a) to (e); ●The above compounds (b) to (f); and ●The above compounds (b) to (e); as well as its pharmaceutically acceptable salts and solvates It may be selected from the following.

[0052] The present invention provides a pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in a mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0053] Compounds of formula I have anticancer activity. Therefore, the present invention is as follows: ● Compounds of formula I or their pharmaceutically acceptable salts or solvates, for use in pharmaceuticals. ● Use of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of drugs for the treatment of cancer. ● A compound of formula I or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer. A method for treating cancer, characterized by administering an effective amount of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof. To provide.

[0054] In each of the above uses, compounds for use, and methods of treatment, cancer is referred to as adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumors, CNS tumors, breast cancer, Castleman disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastric cancer. Cancer, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, renal cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g., acute lymphoblastic, acute myeloid, chronic lymphoblastic, chronic myeloid, chronic myelomonocytic), liver cancer, lung cancer (e.g., small cell or non-small cell), pulmonary carcinoid tumors, lymphoma (e.g., cutaneous), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, stomach cancer Cancer may be selected from one or more of the following groups: testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms' tumor.

[0055] In some embodiments of the present invention, which may be referred to herein, the cancer may be selected from colorectal cancer and gastric cancer.

[0056] The word “comprising” as used herein may be interpreted as requiring the features mentioned but not limiting the presence of other features. Alternatively, the word “comprising” may refer to a situation in which only the enumerated components / features are intended to exist (for example, the word “comprising” may be replaced by the expression “consists of” or “consists essentially of”). It is explicitly intended that both broader and narrower interpretations may apply to all aspects and embodiments of the invention. In other words, the word “comprising” and its synonyms may be replaced by the expression “consists of” or “consists essentially of” or their synonyms, and vice versa.

[0057] The expression "essentially consisting of" and its pseudoonyms may be interpreted herein as referring to a substance that may contain small amounts of impurities. For example, the substance may be 90% or higher in purity, e.g., 95% or higher in purity, e.g., 97% or higher in purity, e.g., 99% or higher in purity, e.g., 99.99% or higher in purity, e.g., 99.999% or higher in purity, e.g., 100% in purity.

[0058] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context makes it clear otherwise.

[0059] References to compounds of formula I in this specification (in any aspect or embodiment of the present invention) include references to such compounds themselves, tautomers of such compounds, and pharmaceutically acceptable salts or solvates of such compounds, or pharmaceutically functional derivatives.

[0060] Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the compound of formula I with one equivalent or more of a suitable acid or base, either in a solvent or in a salt-insoluble medium, and then removing the solvent or medium using standard techniques (e.g., under reduced pressure, by freeze-drying, or by filtration). Salts may also be prepared by exchanging the counterions of the compound of formula I in salt form with other counterions, for example, using a suitable ion-exchange resin.

[0061] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, as well as salts derived from metals (e.g., sodium, magnesium, preferably potassium and calcium).

[0062] Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, aryl sulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, and camphor. Sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D-gluconic acid) Glucolic acid, glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphate, methanesulfonic acid, 1-hydro Examples include acid addition salts formed with xy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0063] Specific examples of salts include salts derived from mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid); organic acids (e.g., tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acid, etc.); and metals (e.g., sodium, magnesium, preferably potassium and calcium, etc.).

[0064] As mentioned above, all solvates of the compound and its salts are also encompassed by Formula I. Preferred solvates are those formed by the incorporation of molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as the solvating solvent) into the solid structure (e.g., crystalline structure) of the compound of the present invention. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol), and dimethyl sulfoxides. Solvates can be prepared by recrystallizing the compound of the present invention in a solvent or a mixture of solvents containing the solvating solvent. In any given case, whether a solvate has been formed can be determined by subjecting the crystals of the compound to analysis using well-known standard techniques (e.g., thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography).

[0065] Solvates can be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, examples of which include hemihydrates, monohydrates, and dihydrates.

[0066] For a more detailed discussion of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0067] As defined herein, “pharmaceutically functional derivatives” of the compounds of formula I include ester derivatives and / or derivatives that have or provide the same biological function and / or activity as any related compound of the present invention. For the purposes of the present invention, the term also includes prodrugs of the compounds of formula I.

[0068] The term “prodrug” for related compounds of Formula I includes any compound that, after oral or parenteral administration, is metabolized in vivo to form an experimentally detectable amount of that compound within a predetermined time frame (e.g., within a 6-24 hour dosing interval, i.e., once to four times per day).

[0069] Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound so that the modification is cleaved in vivo when the prodrug is administered to a mammalian subject. The modification is generally achieved by synthesizing the parent compound with the prodrug substituent. Prodrugs include compounds of formula I in which a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group in the compound of formula I is bonded to any group that may be cleaved in vivo and regenerate a free hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group, respectively.

[0070] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs," pp. I-92, Elsevier, New York-Oxford (1985).

[0071] For simplicity, compounds of formula I, as well as pharmaceutically acceptable salts, solvates, and pharmaceutically functional derivatives of such compounds, will be collectively referred to below as "compounds of formula I."

[0072] The compounds of formula I may contain double bonds, and therefore may exist as E (entgegen) and Z (zusammen) geometric isomers for each individual double bond. All such isomers and mixtures thereof are within the scope of the present invention.

[0073] The compound of formula I may exist as a positional isomer and may exhibit tautomerism. All tautomers and mixtures thereof are included within the scope of the present invention.

[0074] Compounds of formula I may contain one or more chiral carbon atoms and therefore may exhibit optical and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, such as chromatography or fractional crystallization. Various stereoisomers may be isolated by separation of racemates or other mixtures of the compound using conventional techniques (e.g., fractional crystallization or HPLC). Alternatively, desirable optical isomers may be produced by reaction of suitable optically active starting materials under conditions that do not cause racemization or epimerization (i.e., the "chiral pool" method), reaction of suitable starting materials with "chiral auxiliary groups" that can be removed later at an appropriate step, derivatization with homochiral acids (i.e., separation such as kinetic resolution), followed by separation of diastereomer derivatives by conventional means (e.g., chromatography), or by reaction with suitable chiral reagents or chiral catalysts under conditions known to those skilled in the art. All stereoisomers and mixtures thereof are within the scope of the present invention.

[0075] To avoid misunderstanding, in the context of this invention, the term “treatment” includes therapeutic measures or symptomatic treatments for patients requiring such treatment, as well as preventive treatments and / or diagnoses for patients prone to related medical conditions.

[0076] The term “patient” includes references to mammalian patients (e.g., human patients). The terms “subject” or “patient” as used herein are well-known in the art and are used interchangeably herein, and refer to mammals such as dogs, cats, rats, mice, monkeys, cattle, horses, goats, sheep, pigs, camels, and most preferably humans. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disability. However, in other embodiments, the subject may be a healthy person. This term does not imply a specific age or sex. Therefore, adult and neonatal subjects, whether male or female, are intended to be included.

[0077] The term "effective amount" refers to the amount of a compound that produces a therapeutic effect on a patient being treated (for example, sufficient to treat or prevent a disease). The effect may be objective (i.e., measurable by several tests or markers) or subjective (i.e., the subject shows signs of the effect or feels the effect).

[0078] The term "halo," as used herein, includes references to fluoro, chloro, bromo, and iodine.

[0079] Unless otherwise specified, the term "aryl" as used herein means C 6-14 (For example C 6-10 (e.g., aryl groups are included.) Such groups may be monocyclic, bicyclic, or tricyclic, and may have 6 to 14 ring carbon atoms, where at least one ring is aromatic. The bonding site of the aryl group may be via any atom in the ring system. However, if the aryl group is bicyclic or tricyclic, it is bonded to the rest of the molecule via the aromatic ring. 6-14Examples of aryl groups include phenyl, naphthyl, and similar groups (e.g., 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, and fluorenyl). Embodiments of the present invention that may be referred to include embodiments in which the aryl is phenyl.

[0080] Unless otherwise specified, the term "alkyl(alkyl)" refers to unbranched or branched, acyclic or cyclic, saturated or unsaturated hydrocarbyl radicals (e.g., forming alkenyl or alkynyl groups), which may be substituted (e.g., with one or more halo atoms) or unsubstituted. When the term "alkyl" refers to an acyclic group, it is preferably C 1-10 Alkyl, more preferably C 1-6 Alkyl (e.g., ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., branched or unbranched butyl), pentyl, more preferably methyl, etc.). When the term "alkyl" refers to a ring group (or when the group "cycloalkyl" is specified), it is preferably C 3-12 Cycloalkyl, more preferably C 5-10 (For example C 5-7 It is a cycloalkyl compound.

[0081] In certain embodiments of the present invention, where the term "alkyl" is used, it may refer to an unbranched or branched, acyclic, saturated hydrocarbyl radical, which may be substituted (e.g., with one or more halo atoms) or unsubstituted. Where the term "alkyl" refers to an acyclic group, it is preferably C 1-10 Alkyl, more preferably C 1-6 These are alkyl groups (e.g., ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., branched or unbranched butyl), pentyl, more preferably methyl, etc.).

[0082] The term "heteroaryl," as used herein, refers to an aromatic group that contains one or more heteroatoms (e.g., 1 to 4 heteroatoms) preferably selected from N, O, and S (e.g., forming a monocyclic, dicyclic, or tricyclic heteroaromatic group). Heteroaryl groups include 5 to 14 (e.g., 10) member heteroaryl groups and may be monocyclic, bicyclic, or tricyclic, but at least one of the rings is aromatic. However, if the heteroaryl group is bicyclic or tricyclic, it is bonded to the rest of the molecule via the aromatic ring.Heterocyclic groups that may be mentioned include benzothiadiazolyl (2,1,3-benzothiadiazolyl, etc.), isothiochromanil, more preferably acridinil, benzimidazolyl, benzodioxanil, benzodioxepinil, benzodioxolil (1,3-benzodioxolil, etc.), benzofuranil, benzoflazanil, benzothiazolyl, benzoxadiazolyl (2,1,3-benzoxadiazolyl, etc.), benzoxazinil (3,4-dihydro-2H-1,4-benzoxazinil, etc.), and benzo Oxazolyl, benzomorpholinil, benzoselenadiazolyl (2,1,3-benzoselenadiazolyl, etc.), benzothienyl, carbazolyl, chromanil, sinnolinil, furanil, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinil, indolyl, isobenzofuranil, isochromanil, isoindolinil, isoindolyl, isoquinolinil, isothiaziolyl, isoxazolyl, naphthilidinyl (1,6-naphthilidinyl, preferably 1,5-naphthi (e.g., lysinyl and 1,8-naphthilidinyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridadinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolidinyl, quinoxalinyl, tetrahydroisoquinolinyl (1,2,3,4-tetrahydroisoquinolinyl and 5,6 Examples include tetrahydroquinolinyl (e.g., 7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenethyl, thienyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, and 1,3,4-triazolyl), and the like. Substituents on the heteroaryl group may be located on any atom in the ring system containing the heteroatom, where appropriate.The bonding site of the heteroaryl group may be via any atom in the ring system containing a heteroatom (e.g., a nitrogen atom) (where appropriate), or via any atom on a fused carbocyclic ring that may be present as part of the ring system. The heteroaryl group may also be N or S oxidized. Particularly preferred heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenethyl, thiophenyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzimidazolyl, benzthiazolyl, prinyl, synnolinyl, and pterdinyl. Particularly preferred heteroaryl groups include monocyclic heteroaryl groups.

[0083] Unless otherwise specified herein, “heterocyclic ring system” may be a heterocyclic group having 4 to 14 members, e.g., 5 to 10 members (e.g., 6 to 10 members), etc., containing one or more heteroatoms selected from O, S, and N, which may be aromatic, fully saturated, or partially unsaturated, and the heterocyclic group may contain one or two rings. Examples of heterocyclic ring systems that may be mentioned herein include azetidinyl, dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydropyranyl (e.g., 3,4-dihydropyranyl, 3,6-dihydropyranyl), 4,5-dihydro-1H-maleimide, dioxanyl, dioxolanyl, furanyl, flazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, isothiaziolyl, isoxazolidinyl, isoxazolyl, morpholinyl, 1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl, piperazinyl, pyranyl, pyrazinyl, Examples include, but are not limited to, pyridadinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolinyl (e.g., 3-pyrrolinyl), pyrrolyl, pyrrolidinyl, pyrrolidinonyl, 3-sulfolenyl, sulforanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl (e.g., 3,4,5,6-tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylene sulfoxide, tetrazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, thiophenethyl, triazolyl, and triazinanyl.

[0084] Unless otherwise specified herein, “carbocyclic ring system” may be a carbocyclic group having 4 to 14 members, e.g., 5 to 10 members (e.g., 6 to 10 members, e.g., 6 or 10 members), which may be aromatic, fully saturated, or partially unsaturated, and a carbocyclic group may contain one or two rings. Examples of carbocyclic ring systems that may be referred to herein include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, naphthyl, decalinyl, tetralinyl, bicyclo[4.2.0]octanyl, and 2,3,3a,4,5,6,7,7a-octahydro-1H-indanyl. Particularly preferred carbocyclic groups include phenyl, cyclohexyl, and naphthyl.

[0085] Further embodiments of the present invention, which may be referred to, include embodiments in which the compound of formula I is isotope-labeled. However, other specific embodiments of the present invention, which may be referred to, include embodiments in which the compound of formula I is not isotope-labeled.

[0086] The term "isotopically labeled," as used herein, includes references to compounds of formula I in which non-natural isotopes (or unnatural isotopic distributions) are present at one or more positions within the compound. References to "one or more positions within the compound" herein will be understood by those skilled in the art to refer to one or more atoms of the compound of formula I. Therefore, the term "isotopically labeled" includes references to compounds of formula I that are isotopically enriched at one or more positions within the compound.

[0087] The isotope labeling or enrichment of the compound of formula I may be carried out with radioactive or non-radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine, and / or iodine. Certain isotopes that may be mentioned in this regard include: 2 H, 3 H, 11 C, 13 C, 14 C, 13N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 37 Cl, 77 Br, 82 Br, and 125 I is one example.

[0088] When a compound of formula I is labeled or enriched with a radioactive or non-radioactive isotope, compounds of formula I that may be referred to include those exhibiting an isotopic distribution in which at least one atom in the compound has a radioactive or non-radioactive isotope of that atom at a level at least 10% (e.g., 10% to 5000%, particularly 50% to 1000%, and more particularly 100% to 500%) higher than the natural level of that radioactive or non-radioactive isotope.

[0089] Compounds of formula I may be administered by any suitable route, in particular by oral, intravenous, intramuscular, cutaneous, subcutaneous, transmucosal (e.g., sublingual or buccal), rectal, transdermal, transnasal, transpulmonary (e.g., transtracheal or transbronchial), topical, or any other parenteral route, in the form of a pharmaceutical product containing the compound in a pharmaceutically acceptable dosage form. Specific methods of administration that may be mentioned include oral, intravenous, cutaneous, subcutaneous, transnasal, intramuscular, or intraperitoneal administration.

[0090] Compounds of formula I are generally administered as pharmaceutical formulations in mixtures with pharmaceutically acceptable adjuvants, diluents, or carriers, which may be selected with due consideration to the intended route of administration and standard pharmaceutical practices. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may not have adverse side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations are described, for example, in Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration, parenterally acceptable aqueous solutions may be used, which are pyrogen-free and have the required pH, isotonicity, and stability. Suitable solutions are well known to those skilled in the art, and numerous methods are described in the literature. A brief review of drug delivery methods is also described, for example, in Langer, Science (1990) 249, 1527.

[0091] Otherwise, the preparation of a suitable formulation may be routinely achieved by those skilled in the art using routine techniques and / or in accordance with standard and / or accepted pharmaceutical practices.

[0092] The amount of compound I in any pharmaceutical formulation used in accordance with the present invention depends on various factors (e.g., the severity of the condition to be treated, the specific patient to be treated, and the compound used). In any case, the amount of compound I in the formulation may be routinely determined by those skilled in the art.

[0093] For example, a solid oral composition (e.g., a tablet or capsule) may contain 1-99% (w / w) of the active ingredient; 0-99% (w / w) of the diluent or filler; 0-20% (w / w) of the disintegrant; 0-5% (w / w) of the lubricant; 0-5% (w / w) of the flow aid; 0-50% (w / w) of the granulator or binder; 0-5% (w / w) of the antioxidant; and 0-5% (w / w) of the coloring agent. Sustained-release tablets may further contain 0-90% (w / w) of a release-controlled polymer.

[0094] Parenteral formulations (e.g., solutions or suspensions for injection, or solutions for infusion) may contain 1–50% (w / w) of the active ingredient; 50–99% (w / w) of a liquid or semi-solid carrier or vehicle (e.g., a solvent such as water); and 0–20% (w / w) of one or more other additives (e.g., buffers, antioxidants, suspension stabilizers, osmotic regulators, and preservatives).

[0095] Depending on the disorder, the patient to be treated, and the route of administration, the compound of formula I may be administered to patients requiring treatment at different therapeutically effective doses.

[0096] However, in the context of the present invention, the dose administered to mammals, particularly humans, should be sufficient to produce a therapeutic response in the mammal over a reasonable period of time. Those skilled in the art will recognize that the precise dose and composition, as well as the selection of the most appropriate delivery regimen, are influenced, among other things, by the pharmacological properties of the formulation, the nature and severity of the condition being treated, as well as the recipient's health status and intellectual sensitivity, and the potency of the specific compound, the age, condition, weight, sex, and response of the patient to be treated, and the stage / severity of the disease.

[0097] Administration may be continuous or intermittent (by bolus injection). The dose may also be determined by the timing and frequency of administration. When administered orally or parenterally, the dose may vary from about 0.01 mg to about 1000 mg of the compound of formula I per day.

[0098] In any case, physicians or other persons skilled in the art can routinely determine the most appropriate actual dose for each individual patient. The above doses are representative of average cases, and naturally, there may be individual cases where a higher or lower dose range is appropriate, and these are within the scope of the present invention.

[0099] Aspects of the present invention described herein (e.g., the compounds, combinations, methods, and uses described herein) may have advantages over similar compounds, combinations, methods (treatments), or uses known in the art for use in the treatment of the conditions described herein or other conditions, such as being more convenient for physicians and / or patients, more effective, less toxic, better selective, having a broader range of activity, being more potent, having fewer side effects, or possessing other useful pharmacological properties.

[0100] The present invention will be illustrated by the following embodiments, but this should not be considered to limit the scope of the claims. [Examples]

[0101] Preparation Example 1: Extraction and Purification of Morephantin from E. tomentosus L. Leaves of E. tomentosus L. were used for the extraction and purification of morephantin. Briefly, a crude extract was obtained using powdered freeze-dried or freshly harvested leaves as solvents, along with water and methanol. Insoluble residues were removed from the crude extract by centrifugation and filtration. Subsequently, the solvent was removed to produce a concentrated extract, which was then purified using flash column chromatography with silica gel as described below.

[0102] A crude aqueous extract was prepared by adding 50 g of freeze-dried powder to 1 L of distilled water. The powder-water mixture was sonicated for 10 minutes at 75% amplitude (10 seconds on / off) using a Vibra-Cell, VCX130 sonicator. Subsequently, centrifugation and filtration were performed to remove insoluble residues. Then, methanol (MeOH) was added to the filtered extract in a 1:1 (v / v) ratio. The solvent was removed from the extract using a vacuum concentrator to obtain a concentrated extract.

[0103] The extract (2.47 g) was resuspended in MeOH. Silica gel (4 g) was added to the suspension, and the mixture was evaporated to prepare it for dry packing onto a flash column chromatograph. The extract was purified by flash column chromatography (silica gel; CH2Cl2:MeOH = 90:10~80:20). The resulting purified material (138 mg) was further purified by GPC (model: LaboACE LC-5060; column used: JAIGEL-2HR; injection concentration: 13.8 mg / mL; injection volume: 10 mL; flow rate: 10 mL / min) to obtain morephanthin (21.8 mg, 0.0629 mmol) as a brown solid.

[0104] Morephanthin can also be synthesized by the following improved methods, which yield higher yields.

[0105] Crude extract was obtained using powdered lyophilized leaves with ethyl acetate as the solvent. Briefly, 40 g of lyophilized powder was added to 250 mL of ethyl acetate, and the suspension was sonicated for 30 minutes (Fisherbrand® FB15051). The residue in the mixture was precipitated, and the green solution was decanted. The residue was then suspended in another 250 mL of ethyl acetate and sonicated for 30 minutes. This was repeated a total of five times until the solution turned a pale greenish-yellow. The combined organic extract was filtered through Celite® and concentrated under reduced pressure. The crude residue was purified by flash column silica gel chromatography (n-hexane / ethyl acetate = 4:1 to 1:1). Next, charcoal (200 mg) was added to the purified product in ethyl acetate (15 mL), and the mixture was allowed to stand for 30 minutes before being filtered through Celite®. After evaporating the solvent under reduced pressure, gel permeation chromatography (model: LaboAce LC-5060; column used: JAIGEL-2HR-40; injection volume: 10 mL; flow rate: 30 mL / min) yielded two distinct fractions: an inseparable mixture of morephantinin and morephantin, and pure morephantin as a white solid (120 mg, 0.289 mmol).

[0106] Morefantine will be referred to as NYH001 below. [ka]

[0107] Example 2: Synthesis of molephanthin derivatives NYH002-NYH007 Derivatives of molephanthin were produced by esterification reactions. Synthesis of NYH002 [ka]

[0108] To a solution of molephanthin (NYH001) (3.4 mg, 9.82 μmol, 1 equiv) in CH2Cl2 (1 mL), BzCl (6 μL, 52.07 μmol, 5 equiv), Et3N (14 μL, 100.44 μmol, 10 equiv), and DMAP (100 μL, 1.0 mg / mL, 0.82 μmol, 8 mol%) in CH2Cl2 were added at 0°C under nitrogen, and the reaction mixture was stirred at 24°C for 14 hours. The volatile substances were then concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (silica gel, n-hexane:HCl = 70:30) to obtain NYH002 as a yellow oil in 18% yield (0.8 mg, 1.8 μmol) and NYH001 as a brown solid in 71% yield (2.4 mg, 1.8 μmol).

[0109] NYH002 can also be synthesized by the following improved methods, which yield higher yields. [ka]

[0110] To a mixture of NYH001 (190.1 mg, 0.55 mmol, 1.0 equiv), DMAP (6.7 mg, 0.05 mmol, 10 mol%), and triethylamine (459 μL, 3.29 mmol, 6.0 equiv) in anhydrous dichloromethane (2 mL), benzoyl chloride (127 μL, 1.10 mmol, 2.0 equiv) was slowly added at 0°C under argon. The reaction mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then concentrated under reduced pressure. The crude residue was washed with saturated NaHCO3 (10 mL) and subsequently extracted with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated under reduced pressure. The resulting crude material was purified using flash column silica gel chromatography (n-hexane:siRNA=75:25) to obtain NYH002 (228 mg, 92%) as a white solid.

[0111] Synthesis of NYH003 [ka] To a solution of NYH001 (4.5 mg, 12.99 μmol, 1 equiv) in CH2Cl2 (1 mL), pentafluorobenzoyl chloride (19 μL, 131.96 μmol, 10 equiv), Et3N (18 μL, 129.14 μmol, 10 equiv), and DMAP (140 μL, 1.1 mg / mL, 1.26 μmol, 10 mol%) in CH2Cl2 were added at 0°C under nitrogen, and the reaction mixture was stirred at 24°C for 1 hour. The volatile substances were then concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (silica gel, n-hexane:HCl = 70:30) to obtain NYH003 as a colorless oil in 24% yield (1.7 mg, 3.1 μmol).

[0112] NYH003 can also be synthesized by the following improved methods, which yield higher yields. [ka]

[0113] In 1 mL of anhydrous dichloromethane, a mixture of NYH001 (35.8 mg, 0.10 mmol, 1.0 equiv), DMAP (1.2 mg, 0.01 mmol, 10 mol%), and triethylamine (86 μL, 0.62 mmol, 6.0 equiv) was slowly added with pentafluorobenzoyl chloride (30 μL, 0.21 mmol, 2.0 equiv) at 0°C under argon. The reaction mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then concentrated under reduced pressure. The crude residue was washed with saturated NaHCO3 (5 mL) and subsequently extracted with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated under reduced pressure. The crude substance obtained was purified using flash column silica gel chromatography (n-hexane:Â=75:25) to obtain NYH003 (31.8 mg, 57%) as a white solid.

[0114] Synthesis of NYH004 [ka] To a solution of NYH001 (7.3 mg, 21.08 μmol, 1 equiv) in CH2Cl2 (1 mL), 4-(trifluoromethyl)benzoyl chloride (31 μL, 208.69 μmol, 10 equiv), Et3N (29 μL, 208.06 μmol, 10 equiv), and DMAP (1.3 mg, 10.64 μmol, 50 mol%) were added at 0°C under nitrogen, and the reaction mixture was stirred at 24°C for 16 hours. The volatile substances were then concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (silica gel, n-hexane:HCl = 80:20) to obtain NYH004 as a pale yellow solid in 55% yield (6.0 mg, 11.68 μmol).

[0115] NYH004 can also be synthesized by the following improved methods, which yield higher yields. [ka]

[0116] In 1 mL of anhydrous dichloromethane, a mixture of NYH001 (32.8 mg, 0.09 mmol, 1.0 equiv), DMAP (1.1 mg, 9.5 μmol, 10 mol%), and triethylamine (79 μL, 0.57 mmol, 6.0 equiv) was slowly added with 4-(trifluoromethyl)benzoyl chloride (28 μL, 0.19 mmol, 2.0 equiv) at 0°C under argon. The reaction mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then concentrated under reduced pressure. The crude residue was washed with saturated NaHCO3 (5 mL) and subsequently extracted with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated under reduced pressure. The crude material obtained was purified using flash column silica gel chromatography (n-hexane:siRNA = 75:25) to obtain NYH004 (47.6 mg, 97%) as a white solid.

[0117] Synthesis of NYH005 [ka] To a mixture of NYH001 (13.8 mg, 0.04 mmol, 1.0 equiv), DMAP (0.5 mg, 4.0 μmol, 10 mol%), and triethylamine (33 μL, 0.24 mmol, 6.0 equiv) in anhydrous dichloromethane (1 mL), 3,5-bis(trifluoromethyl)benzoyl chloride (14 μL, 0.08 mmol, 2.0 equiv) was slowly added at 0°C under argon. The reaction mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then concentrated under reduced pressure. The crude residue was washed with saturated NaHCO3 (5 mL) and subsequently extracted with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated under reduced pressure. The crude substance obtained was purified using flash column silica gel chromatography (n-hexane:Â=75:25) to obtain NYH005 (21.1 mg, 90%) as a white solid.

[0118] Synthesis of NYH007 [ka] In 1 mL of anhydrous dichloromethane, a mixture of NYH001 (25.0 mg, 0.07 mmol, 1.0 equiv), DMAP (0.8 mg, 7.2 μL, 10 mol%), and triethylamine (60 μL, 0.43 mmol, 6.0 equiv) was slowly added with 4-nitrobenzoyl chloride (27 mg, 0.14 mmol, 2.0 equiv) at 0°C under argon. The reaction mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then concentrated under reduced pressure. The crude residue was washed with saturated NaHCO3 (5 mL) and subsequently extracted with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated under reduced pressure. The crude substance obtained was purified using flash column silica gel chromatography (n-hexane:siRNA = 75:25) to obtain NYH007 (31.2 mg, 87%) as a white solid.

[0119] Example 3: Cytotoxicity assay To test the cytotoxic effects of compounds NYH001-NYH005 in various cancer cell types, different cancer cells were treated with the compounds for 48 hours and analyzed using an MTT assay. For all compounds tested, cell proliferation was found to be suppressed in a dose-dependent manner. The absolute IC of the compounds was also determined. 50 The values ​​were calculated (Table 1, Figures 1A-C). Notably, the inhibitory effect of the novel compounds NYH002-NYH005 was greater than that of the natural compound NYH001 (molefantin), indicating higher activity in suppressing cancer cell survival. The cytotoxic effect of NYH007 was tested in DLD-1 cells, and IC 50 It was found to be 0.35 μM. Table 1 IC of NYH001-NYH005 against different cancer cell lines 50 [Table 7]

[0120] To further confirm the inhibitory effect of the compounds on cancer cell proliferation, a colony formation assay was performed. Cells were treated with various doses of the compounds and grown for 7–10 days until colonies formed. Colonies were fixed and stained with 0.5% w / v crystal violet containing methanol. After rinsing the cell culture plates with distilled water, they were scanned for quantification. The number of colonies was quantified using ImageJ software.

[0121] The results showed that the compounds could significantly reduce the clonal activity of cells in a dose-dependent manner. Similar to the MTT cell viability assay, the novel compounds NYH002-NYH005 had a greater effect on cell viability compared to NYH001. In particular, NYH002 and NYH003 did not induce any colony formation at concentrations down to 1 μM in some cell lines (Figure 2A-E).

[0122] Example 4: Morphological changes by live cell imaging To investigate cell morphological changes and cell fate, cells were seeded in 12-well tissue culture plates, treated with different concentrations of compounds, and placed on a thermally controlled stage of a Zeiss Axiovert 200M microscope. The temperature was maintained at 37°C and the CO2 concentration at 5%. Phase-contrast images were acquired at 15-minute intervals for 72 hours.

[0123] While untreated cells were able to grow and proliferate healthily during live-cell imaging, cancer cells treated with compounds NYH001-NYH003 underwent dose-dependent inhibition of growth and cell death. Cancer cells were observed to exhibit rounding of cells and delayed mitosis, eventually leading to cell shrinkage, membrane bleb formation, and apoptosis-like cell death (Figure 3).

[0124] Example 5: Cell migration and invasion assay Cell migration and invasion are major factors that promote cancer cell metastasis. To investigate the effects of compounds on cell motility and invasion, Transwell migration and invasion assays were performed. Transwell assays were performed using 8 μm pore size Transwell inserts (Corning Costar). For the migration assay, 7.5 x 10⁶ cells treated with the compound were used. 4 ~1.5x10 5 Individual cells were added to the upper chamber in serum-free medium. In the invasion assay, the Transwell insert was first coated with Matrigel before cell seeding. For both assays, the lower chamber was filled with cell medium containing 10% FBS. After incubation at 37°C for 24 hours, cells that did not migrate or invade were removed from the upper chamber. Migrating or invading cells were fixed in the lower chamber with 4% paraformaldehyde, stained with crystal violet, and imaged under a microscope. The bound crystal violet was eluted with 33% acetic acid, and the eluent was transferred to a 96-well plate for absorbance measurement at 590 nm using a plate reader.

[0125] The Transwell assay demonstrated that treatment with a single compound dose-dependently inhibited cancer cell migration (Figure 4A-D), and that NYH002-NYH005 showed a more potent inhibitory effect compared to NYH001.

[0126] Furthermore, the compound also reduces the invasiveness of cells in the tested cell lines (Figure 5A-B).

[0127] Example 6: Induction of cell cycle arrest and apoptosis The cell cycle distribution of DLD-1 cells treated with the compound was further investigated by flow cytometry. In short, cells were harvested 24 hours after treatment with NYH001-NYH005 and fixed with 70% ethanol. The cells were washed and suspended in PBS containing propidium iodide and RNase for 30 minutes. The cell cycle distribution was determined using a flow cytometer with CellQuest Pro Software. Cytometry results were analyzed using FlowJo software.

[0128] The percentage of cells in the G1, S, or G2 / M phase after exposure to the compound was evaluated. The percentage of compound-treated DLD-1 cells in the G2 / M phase was significantly higher than that in the control DMSO group, suggesting that the compound induced cell cycle arrest in the G2 / M phase. The cell population in the S phase also increased slightly, indicating that the compound may also delay the cell cycle in the S phase (Figure 6).

[0129] To determine the mode of cell death induced by NYH001-NYH003 in cancer cells, the expression of pro-apoptosis markers (e.g., cleaved PARP and cleaved caspases 3 and 7) and autophagy markers LC3B and ATG7 was quantified by Western blotting. The compounds NYH001-NYH003 were found to dose-dependently induce the production of both pro-apoptosis and autophagy markers in DLD-1 cells. Western blotting results suggest that the compound-induced cell death is somewhat involved in apoptosis and autophagy (Figure 7).

[0130] Example 7: Tumor spheroid proliferation assay The tumor spheroid proliferation assay is established to create an environment more physiologically relevant to the tumor microenvironment and is therefore considered more representative of in vitro drug screening. In this assay, small tumor spheroids containing DLD-1 cells were created by seeding 8,000 cells onto agarose-coated 96-well tissue culture plates and then centrifuging at 800 g for 5 minutes. This method allows for the creation of small spheroids with similar morphology and dimensions. The spheroids were then grown for 15 days under normal conditions or under treatment with NYH001-003. 50% medium changes with or without the compound were performed every 3 days.

[0131] The area of ​​spheroids was measured using Fiji. It was clear that the proliferation of spheroids treated with NYH001-NYH003 was suppressed in a dose-dependent manner (Figures 8 and 9).

[0132] Example 8: Wound closure assay A wound closure assay was performed to determine the effect of NYH001-003 on cell motility. AGS cells were grown in the wells of a 4-well silicon insert (Ibidi) until 100% confluence. The wells were separated by a 500 μm wall, and removing the insert created a gap of approximately 500 μm. Cells were washed with PBS to remove dead and suspension cells before treatment with different concentrations of NYH001-003 or DMSO. Cell migration into the gap was monitored for 24 hours by live-cell imaging. Wound closure was analyzed by Fiji. The data showed that NYH001-003 can efficiently inhibit cell motility in a dose-dependent manner and therefore may reduce cancer cell metastasis (Figures 10A-10C).

[0133] Example 9: Suppression of tumor growth in HCT116 and DLD-1 subcutaneous tumor xenograft mouse models 1 × 10⁻⁶ Hanks equilibrium salt solution in Matrigel, 1:10⁻⁶ 6 Individual HCT116 or DLD-1 cells were subcutaneously injected into the right flank of female J:Nu non-inbred nude mice (5-6 weeks old). Tumor volume was 50-100 mm².3 When the target was reached, mice were assigned to treatment groups (4-5 mice per group). For 3 weeks, vehicle control (ethanol:Kolliphor EL:saline = 1:1:8), NYH001 (25 mg / kg), NYH002 (25 mg / kg), or 5-fluorouracil (5-FU, 25 mg / kg) was administered intraperitoneally every other day. The body weight of the mice was measured daily, and tumor size was measured twice a week. Equation: Volume = (long side × short side) 2 ) / 2mm 3 Tumor size was calculated using [a specific method / tool]. Mice were sacrificed and tumors were excised at the end of the 3-week treatment period. All procedures were approved by the NTU Institutional Animal Care and Use Committee (IACUC) and performed in accordance with IACUC Protocol A20001.

[0134] The results showed that mice treated with NYH002 had significantly suppressed tumor growth (Figures 11 and 12). After 21 days of treatment, the mean tumor volume was reduced by 46.5% and 51.9% in HCT116 and DLD-1 xenograft mice, respectively, compared to mice treated with vehicle control (Figures 11C and 12C). The mean tumor weight was also reduced by 49.3% and 57.3% in HCT116 and DLD-1 xenograft mice (Figures 11D and 12D). The reduction in tumor size was more pronounced than in mice treated with 5-FU, a common chemotherapeutic agent used to treat colon cancer. 5-FU treatment resulted in a 10.4% and 32.3% reduction in tumor volume and a 21.9% and 38.7% reduction in tumor weight in HCT116 and DLD-1 xenograft mice, respectively, compared to control.

[0135] The efficacy of NYH001 treatment in HCT116 xenograft mice was also evaluated. NYH001 treatment suppressed tumor growth more effectively than 5-FU treatment, but was less effective than NYH002. Mean tumor volume and weight decreased by 35.4% and 41.7%, respectively, in HCT116 xenograft mice (Figures 11C and 12D). None of the treatments caused adverse changes in body weight throughout the experiment (Figures 11E and 12E).

[0136] Overall, the results showed that NYH002 treatment had superior anticancer efficacy and minimal toxicity in vivo, providing improved anticancer efficacy compared to morephantine (NYH001) and 5-FU.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, R1 represents -C(O)R3, and R ２ This is -C(O)R 3 or -C(O)C(=CH ２ )CH ３ This indicates, and R ３ represents an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is either unsubstituted or halo, C １－３ Alkyl, and NO ２ It is substituted by one or more groups selected from, where C １－３ Alkyls are either unsubstituted or substituted with one or more halo groups, and the term "alkyl" refers to an unbranched or branched acyclic saturated hydrocarbyl radical. A compound thereof, or a pharmaceutically acceptable salt or solvate thereof.

2. R ３ represents an aryl or hetero cyclic ring system, wherein each of the aryl and hetero cyclic ring systems is unsubstituted or substituted by one or more groups selected from halo, C １－３ alkyl, and NO ２ wherein C １－３ alkyl is unsubstituted or substituted by one or more halo groups, A compound of formula I as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. R ３ However, it is an aryl, where the aryl is either unsubstituted or halo, C １－３ Alkyl, and NO ２ It is substituted by one or more groups selected from, where C １－３ Alkyl groups are either unsubstituted or substituted with one or more halo groups. The compound of formula I as described in claim 2, or a pharmaceutically acceptable salt or solvate thereof.

4. R ３ However, it is phenyl, and here phenyl is either unsubstituted or F, C １ Alkyl, and NO ２ It is substituted by one or more groups selected from, where C １ Alkyl groups are either unsubstituted or substituted with one or more halo groups. The compound of formula I described in claim 3, or a pharmaceutically acceptable salt or solvate thereof.

5. R ２ However, -C(O)C(=CH ２ )CH ３ To show, A compound of formula I as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

6. The following compounds: Table 1 Table 2 Selected from a list consisting of, A compound of formula I as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. The following compounds: Table 3 Table 4 Selected from a list consisting of, The compound of formula I as described in claim 6, or a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical formulation comprising a compound of formula I as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, in a mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier.

9. Use of a compound of formula I as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a drug for treating cancer.

10. A cancer treatment agent comprising a compound of formula I as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof.

11. The aforementioned cancers include adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumor, CNS tumor, breast cancer, Castleman disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, and gastric cancer. A therapeutic agent according to claim 10, selected from one or more of the group selected from cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, renal cancer, laryngeal cancer, hypopharyngeal cancer, leukemia, liver cancer, lung cancer, pulmonary carcinoid tumor, lymphoma, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, stomach cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms' tumor.

12. The therapeutic agent according to claim 11, wherein the cancer is selected from colorectal cancer and gastric cancer.

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